globus pallidus

By: Laurence Poliquin-Lasnier
R4 Neurology
 General principles
 Terrestrial biotoxins
 Metal intoxications
 Organic chemicals intoxications
 Marine Neurotoxins
General Principles
 Peripheral neuropathy of the distal axonopathy type is the most common
presentation of North American neurotoxic disease
 Detailed history is important to establish causative agent
 Virtually all neurotoxic disease improves or stabilizes following withdrawal
from exposure
 Progression of illness for years following removal strongly suggests the
condition is not due to an exogenous chemical
 Laboratory data are available for heavy metals and drugs of abuse, but not for
most industrial or environmental agents and electrodiagnostic studies are nonspecific
 Age and preexisting conditions (eg.: hereditary neuropathy) can increase
vulnerability to neurotoxic agents
 Eg.: a person with Charcot-Marie-Tooth disease given vinca alkaloid tx may develop
an unusually severe neuropathy
Vulnerability of
peripheral nervous
system motor unit and
subcellular structures
Terrestrial biotoxins
1. Bacterial
2. Clostridial
3. Envenomation
4. Botanical
1-Bacterial toxin: Diphteria
 Diphtheria is an acute, contagious disease caused by the grampositive bacillus Corynebacterium diphtheriae
 There are two forms of symptomatic infection (respiratory and
cutaneous) and an asymptomatic carrier state
 The respiratory form of diphtheria causes the characteristic
pseudomembranous pharyngitis
 Other common complications of severe infection include myocarditis,
neuritis, and less often nephritis
 C. diphtheriae solely lives in the mucous membrane and skin of
humans and infects via airborne respiratory droplets, direct contact
with respiratory secretions of symptomatic individuals, or infected
skin lesions
 Asymptomatic carriers are an important mode of transmission
 What is the most common severe complication of C. diphteria?
 Acute demyelinating polyneuropathy >most common severe complication
 Diphtheritic neuropathy is an uncommon
disease in Western Europe and the
United States due to vaccination
 Large epidemic from 1990 to 1995 was
reported in the former Soviet Union
 Fatality rate 2-3%
 15% incidence of neurologic complications was reported in adults
 Correlation between the severity of the diphtheritic polyneuropathy and the
severity of the diphtheria infection
 Latency in development of diphtheritic polyneuropathy varies from 18 to 46
days from the initial infection (mean 30 days)
 Approximately 2/3 of patients who developed a diphtheritic polyneuropathy
had a preceding serious diphtheria infection with both cardiac and renal
 Neurologic manifestations of diphtheria are biphasic
Early bulbar disturbance (wks 3 to 5) with cranial neuropathies (ocular and lower CN
may be affected)
Late motor weakness in the trunk and extremities (wks 5 to 8)
 Improvement in cranial nerves occurs with ongoing motor disturbance in trunk
and extremities
 Weakness in the limbs can be both proximal and distal with
associated atrophy in severe cases
 Paralysis of the diaphragm and respiratory failure can occur
 Sensory disturbances in all modalities with paraesthesias of
distal extremities and often a sensory ataxia
 Hypotonia, hyporeflexia, and downgoing plantar responses
 Significant abnormalities of parasympathetic and
sympathetic function are often present and more common
with severe cases
 Pathogenesis: paranodal
demyelination and
segmental demyelination
both at ventral and dorsal
spinal roots and peripheral
 Large DDx
 Diagnosis: Isolation of C. diphtheriae on culture with
toxigenic testing with nasopharyngeal swab from the
patient and his/her contacts
 C. diphtheriae requires special culture median containing
 Elek test is performed to determine if the bacillus
produces toxin and is an important test in the diagnostic
 Measurement of serum antibodies to diphtheria toxin may
also help assess the probability of diphtheria
 PCR available for confirmation
 NCS: demyelinating
 Treatment:
 Antibiotic therapy in combination with antitoxin
administration within 48 hours of diagnosis to decrease
the chances of developing diphtheritic polyneuropathy
 Antitoxin does not neutralize toxin that is already bound
to tissues -> delaying its administration is associated
with an increase in mortality risk
 Antibiotics to eradicate and avoid transmission
Case #1
 57-year-old farmer was admitted to the hospital with a 1week history of right lower extremity muscular rigidity that
over a period of a week started to spread to his axial
muscles including the neck, back, and abdominal muscles
 He reported stepping on a nail in the barn 2 weeks prior to
the onset of symptoms and still had an open festering
wound at the puncture site
 He then developed laryngospasms that led to respiratory
compromise requiring intubation
 His sensorium remained clear
 Diagnosis?
2- Bacterial toxin: Clostridial->
 Clostridium tetani
 Anaerobic, gram positive rod
 Metabolizes in anaerobic conditions and reproduces via
spores that can survive in aerobic conditions
 The spores are the common mode of transmission
 The bacterium survives in soil and in the intestines and
feces of animals, from which the spore invades the body
through seemingly insignificant wounds and subsequently
Early manifestations of generalized tetanus include rigidity of the masseter muscles (trismus aka lockjaw)
and of facial muscles with a distinct straightening of the upper lip causing a grimacing posture to the face
(risus sardonicus)
Frequent localized stiffness near the site of the penetrating wound followed by rigidity of the axial muscles
involving the neck, back muscles (opisthotonus), and abdomen
With progression, extremities become stiff with relative sparing of the distal muscles
Spasms can be significant enough to break long bones of the extremities
Paroxysmal reflex spasms can occur in severe cases, generally in response to voluntary movements or to
external and internal stimuli
In severe cases, muscles of deglutition may also go into trismus, causing dysphagia and dysarthria ->
laryngospasms can lead to respiratory compromise and asphyxia
Over a period of approximately 2 wks, the severity of symptoms can worsen, and by 4 weeks recovery
usually begins
A hypersympathetic state may be a manifestation of more severe cases with fluctuations of BP and HR
Profuse sweating, high fever, and hypersalivation are also common signs of autonomic instability
 Neonatal tetanus usually occurs in the generalized form and
tends to carry a high mortality rate
 The most common symptoms of neonatal tetanus are a
failure to suck and muscular twitching
 Neonatal tetanus generally develops in the first 2 wks of life
in children born to mothers who have been poorly
 These infants often have umbilical stump infections
 In some underdeveloped countries, some practices occur in
the birthing process that put infants at risk, including the
application of clarified butter with contaminated dung fuel on
umbilical cords
 Pathogenesis:
 Tetanus is transported to the
spinal cord from the
neuromuscular junction and
then transported by
transcytosis to the inhibitory
Renshaw cell and to the
upper motor neurons
 Blocks the release of glycine
and GABA from inhibitory
neurons, leading to spastic
paralysis -> no relaxation of
the antagonistic muscle
during normal contraction
 Diagnosis: Clinical
 Positive spatula test on physical: reflex spasm of the masseter muscle on
touching the posterior pharyngeal wall
 Continuous, spontaneous motor unit discharges on EMG reported but not
diagnostic of tetanus
 In some serious cases, elevated CSF protein and immunoglobulin levels have
been documented
 C. tetani can be cultured in about 1/3 of confirmed cases from wounds
 PCR assays for neurotoxin gene fragments available
 The presence of serum antitoxin of 0.01 unit per mL or higher is considered
protective and makes a diagnosis of tetanus unlikely
 Prognosis: related to degree of autonomic instability and type of wound/injury.
Burns, infected umbilical stumps, and compound fractures are frequently
related to a poor prognosis
 Treatment: elimination of the source of toxin, toxin neutralization, control of
muscle rigidity and spasms, and ventilatory support
 If no wound is found, careful examination for signs of parenteral drug abuse,
otitis, and careful rectal and vaginal examinations are recommended
 A retained foreign body may result in continuous toxin production
 Although controversial, the use of metronidazole (500 mg IV every 6 hours for
7 to 10 days) is the drug of choice
 Penicillin has a central GABA antagonistic effect and can worsen spasms
 Administration of human tetanus immunoglobulin is recommended before
manipulating a wound -> recommended dose is 500 units IM
 Combined intrathecal (1000 units) and IM antitetanus immunoglobulin
administration gives better clinical outcomes than IM administration alone
Bacterial toxins
 Another clostridial toxin -> clostridium botulinum
(covered in neuromuscular talk) with the typical
descending flaccid paralysis
 Anthrax (Bacillus anthracis) -> hemorrhagic
 With the exception of the coral snake, all the venomous snakes in the United
States are pit vipers (rattlesnakes, cottonmouths, and copperheads)
 The incidence of venomous snake bites in the United States is approximately
7000 to 8000 per year, but only 5-6 result in death
 Confident diagnosis of a venomous snakebite requires a positive identification
of the snake and recognition of the clinical manifestations of the
 Rarely a snake will be brought in alive or dead for inspection at the clinic
 Caution should be taken handling dead snakes as a bite reflex can occur even
after the death
 Envenomation does not always occur with venomous
snakes (25% of all viper bites are dry)
 Toxins
 α-Bungarotoxin and cobrotoxin: postsynaptic blockade of
acetylcholine receptors (AChRs)
 β-Bungarotoxin and crotoxin: presynaptic inhibition of acetylcholine
(ACh) release
 Local pain, swelling, and erythema at site of the bite
 Focal weakness or compartment syndrome
 Diffuse proximal weakness resembling myasthenia gravis
 Ptosis, cranial neuropathies, myokimia, dysphagia, areflexia,
fasciculations, respiratory distress
 Systemic manifestations, including hypotension and shock
 With pit viper envenomations, incision and suctioning at
the bite site within minutes can remove venom
 Antivenin, most effective when given within 4 hrs of bite
 Beware of anaphylactic reaction
3- Envenomation/Scorpion
 Tityustoxin, produced by Tityus serrulatus,
causes presynaptic facilitation of ACh release
and postsynaptic activation of voltage-gated
sodium channels
 Local pain and erythema at site of the bite
 Excess cholinergic activity: salivation,
lacrimation, urinary incontinence, defecation,
gastroenteritis, and emesis (SLUDGE)
 Local paresthesias, followed by diffuse
paresthesias (thalamic involvement) ,
fasciculations, tremors, hyperreflexia, ptosis,
nystagmus, blurred vision, dysarthria, and
 Pandysautonomia: hypertension, hyperthermia,
hypersalivation, diaphoresis, urinary frequency,
fecal urgency
3- Envenomation/Scorpion
 Treatment: supportive care
 Anti-venin
 With the use of Centruroides antivenin, moderate to
severe neurologic symptoms may reverse in 15 to 90
3- Envenomation/Female
black widow spider
(Latrodectus mactans)
Most important spider to cause potentially significant
Poorly lighted area-> often sting genitalia
Toxin: α-latrotoxin, causing presynaptic facilitation of
ACh release and depletion of Ach
Erythema at site of the bite, intense pain, and
involuntary muscle spasms involving the limbs, trunk,
and diaphragm (latter causing respiratory arrest),
dysarthria, chest pain
Autonomic symptoms: hypertension, piloerection,
diaphoresis, brochospasm
Acute symptoms increase in severity during the first day
after a bite. Most symptoms generally decline after 2 to
3 days, but some mild residua may continue for several
Tx: antivenin
Case #2
12-year-old girl presents to the ER with progressive gait instability, ascending weakness,
shortness of breath on exertion, slurred speech, and swallowing difficulties over 3 days
No GI or pulmonary symptoms, nor fever preceding the onset of symptoms
On examination, she was alert with some facial weakness, dysarthria, and diffuse 3-4/5
weakness worse in the legs than the arms
Reflexes were absent, and she had no sensory abnormalities
A neurologist saw the patient in the ER and thought Guillain-Barré syndrome was likely
CSF analysis and NCVs including repetitive stimulation were normal, except for lowamplitude CMAPs, making the diagnosis of Guillain-Barré syndrome unlikely
A careful examination of the patient with a comb revealed a tick at the nape of her neck.
Within hours of its removal, the patient started to get better and eventually made an
uneventful recovery within a week
3- Tick paralysis
 Results from inoculation of toxin contained in the tick saliva at the
time of a blood mea
 Tick paralysis is associated with over 40 species of tick worldwide,
including five species in North America; yet only four tick species
cause human disease
 The tick species responsible for most cases of human tick
paralysis in the United States and Canada are Dermacentor
andersoni (the Rocky Mountain wood tick), and Dermacentor
variabilis (the American dog tick)
 Other areas of the body involved include the nose, ear canals, and
genital area
 The incidence is most frequent in spring and summer
3-Tick paralysis
Acute ascending paralysis over days without sensory symptoms
Unlike Lyme disease, symptoms regularly resolve after tick is removed
Symptoms usually begin 2 to 6 days after the tick becomes attached
Constitutional symptoms such as fever are lacking, but generalized fatigue is not an
uncommon initial symptom
Often mistaken for GBS-> Gait instability -> falling -> total inability to walk is a common
presentation over a couple of days and may quickly involve respiratory muscles and
cranial and bulbar muscle -> intubation
Weakness worse in the LE and ass. with hypotonia and hypo/areflexia
Isolated facial weakness has been described, although more diffuse involvement of the
cranial nerves leading to ophthalmoplegia, dysarthria, and dysphagia is more common
Reports in children of ataxia, mild encephalopathy, minor sensory disturbances
3- Tick paralysis
Pathogenesis not entirely understood but thought to block
axonal Na+ channels and to inhibit the release of ACh at
presynaptic motor nerve terminals, causing total neuromuscular
EMG/NCVs are well described and suggest axonal involvement
with evidence of denervation
CMAPs are of low amplitude and improve with the removal of
the tick as does the clinical status
Treatment: Remove the tick
Coating the tick with petroleum jelly to make it release its hold
is helpful and one should attempt to grasp the tick as close to
skin as possible and make sure to remove all of the tick's
capitulum (head)
Detection and removal of the tick usually results in rapid
improvement (hours to 1 or 2 days) in the patient's condition
Antiserum is generally neither recommended, nor necessary
4- Botanical toxin:
Amanita mushrooms
After consumption, there are initially no signs of toxicity, but a severe gastroenteritis
ensues after about 6 to 12 hrs with N/V, abdo cramping, and diarrhea
For the next 24 to 48 hrs, the patient may improve clinically, giving a sense of false hope
as during that time renal and hepatic function deteriorate
Toxicity begins upon active transport into hepatocytes where it binds to and inhibits RNA
polymerase II, leading to inhibition of protein synthesis and ultimately hepatocyte death
Hepatotoxicity and renal failure develop in the next 3 to 5 days, followed by secondary
metabolic encephalopathy
Neurologic compromise may be related to direct effects of α-amatoxin and indirect
effects of brain edema from liver failure
The key psychoactive constituents in these mushrooms are ibotenic acid, muscimol, and
The GABA receptor agonist, muscimol, is somewhat sedating, Ibotenic acid binds to
glutamate receptors and induces an agitated delirium
Tx: supportive
 General principles
 Terrestrial biotoxins
 Metal intoxications
 Organic chemicals intoxications
 Marine Neurotoxins
Metal intoxication
 Arsenic
 Lead
 Manganese
 Mercury
A few caveats…
principles of
industrial and
Case #3
 A 62-year-old woman was evaluated for a 3-year history of slowly
progressive, ascending, distal lower limb paresthesias. She was
on no medications and did not give a history of potential toxic
exposure. Her examination was remarkable for decreased
perception of vibration and position at the toes and a graded
decreased perception of pinprick and touch distal to the mid-shin
level. Her ankle jerks were absent. No other abnormalities were
noted on her general and systemic examination. Nerve
conductions studies revealed an axonal, symmetric, lengthdependent, predominantly sensory PN. Extensive investigations
examining various causes of neuropathy were unrewarding. A
urine heavy metal screen was, however, remarkable for a 24-hour
arsenic excretion of 862 μg (normal: less than 120 μg/24 h)
 What’s your diagnosis?
Case #3
 Elevation in urinary arsenic excretion is sometimes due to
the organic, nontoxic form resulting from prior seafood
 Within hours of seafood ingestion total urinary arsenic
concentration may be in the range of 100 μg/L to 10,000
 Seafood should be avoided for 3 to 4 days prior to a urine
arsenic determination
 This patient admitted to seafood ingestion during and prior
to the urine collection and a repeat collection was normal
 May be due to poisoning or man-made sources (eg.: metal
smelting, mining, abrasive blasting, pesticide manufacturing,
combustion of coal, and burning of agricultural wastes, burning of
chromated copper arsenate-treated wood in fireplaces or wood
stoves), found in tap water in Bangladesh
 Arsenic is also used in the ceramic industry and manufacture of
semiconductors, light-emitting diodes, transistors, lasers, computer
microchips, and microwave circuits
 Shortly after ingestion, arsenic is stored in reticuloendothelial
system, kidney and intestines and is slowly released
 Slow excretion via kidney and feces
 Deposited in hair within 2 wks and remains in hair for years
 Clinical features
 Acute or subacute exposure: abdo pain, nausea, vomiting,
hyperthermia, headaches, anxiety, vertigo, possibly seizure,
 Fatal acute poisoning: precipitous development of lethargy and coma
followed by death in few days, may be due to diffuse edema and/or
hemorrhagic encephalopathy
 Low-dose chronic exposure: similar clinical features but much less
severe (abdo pain, vertigo, longstanding cognitive disturbance, persistent
headaches and development of peripheral neuropathy
 Optic neuropathy: possible delayed manifestation
 Metallic taste
 Mee’s lines: white lines in nails, usually appear 2-3 wks after exposure
 Peripheral neuropathy
 Painful, distal, axonal, may mimic GBS in severe cases
 Glove-stocking distribution with involvement of small and large fibers leading
to pseudoathetosis and allodynia
 Distal weakness
 Hypo/areflexia
 Associated with exfolliative dermatitis
 24h urine heavy metal arsenic level (may be falsely elevated
by shellfish ingestion), serum levels unreliable
 Increased arsenic levels in nail clippings or pubic hair
(preferable to scalp as less chance of environmental
 Acute: supportive (hydration, pain control, gastric lavage)
 Chelation therapy with dimercaprol or its water soluble
derivative dimercaptosuccinic acid (DMSA); or penicillamine
(best if started early)
Inorganic lead
 Children absorb lead more effectively than adults
 Lead reaches bones, teeth, and soft tissue, and long-term storage occurs in
the skeletal system
 Bone resorption causes reentry of lead into the blood stream with the potential
of causing delayed deleterious effects
 Pregnancy, lactation, menopause, osteoporosis, and other events that lead to
increased bone resorption may lead to increased blood level in individuals
with substantial amount of lead stored in bone
 Found in old paints, drinking water through dissolution of lead in old plumbing,
manufacture of lead-acid batteries, battery recycling plants, crushing and
smelting of lead and other metal ores, radiation shielding, blasting and
sanding of lead-coated surfaces, and soil contaminated from vehicle exhaust
and industrial emissions, ammunition, cosmetics
Inorganic lead
 Acute intoxicatio(90 μg/dL): acute GI illness, confusion,
lethargy, seizures, coma, and respiratory arrest with
high levels of exposure
 Chronic, low-level exposure (10 μg/dL): gradual onset
of listlessness, behavioral changes, psychomotor
slowing, sleep disturbance, seizures, gait disorder
characterized by clumsiness or frank ataxia
Inorganic lead
 Adults
 Polyneuropathy: predominantly motor neuropathy, with
distal weakness, atrophy, and fasciculations (pain
 Motor manifestation may be more prominent in upper
extremities: may present with bilateral wrist drop, with or
without distal lower limb weakness, often asymmetric
 Motor neuropathy commonly involves radial nerve
(wristdrop is most common)
 There may or may not be sensory symptoms,
predominantly paresthesias (allodynia and dysesthesias
are uncommon)
Inorganic lead
 Laboratory diagnosis
 Microcytic, hypochromic anemia
 Basophilic stippling of red blood cells on blood smear
 Renal insufficiency, azotemia
 Elevated blood levels of lead
 Lead interferes with hemoglobin synthesis by inhibiting the enzymes δaminolevulinic acid dehydratase and ferrochelatase and results in
elevated free erythrocyte protoporphyrin (FEP) which is more accurate
than serum lead levels for chronic toxicity but because of poor
sensitivity, serum lead level is still the preferred screening method
 Treatment: chelation with DMSA, intravenous calcium disodiumEDTA, or penicillamine
 Exposure
 Primary source of exposure (occupational): miners, ferromanganese
smelting plant workers, workers in manganese ore-crushing plants,
welders, and those involved in the manufacture of dry batteries
 Patients receiving total parenteral nutrition containing manganese
 Pathology: neuronal loss and gliosis affecting the globus pallidus and
subthalamic nucleus; uncommon involvement of substantia nigra
 Main source of disposal is biliary excretion: patients with biliary atresia or
chronic liver disease are prone to develop manganese toxicity (may explain
high T1 signal in pallidum observed in chronic liver disease)
 Mechanism: oxidative stress generated through mitochondrial perturbation,
NMDA-mediated excitotoxicity, and disruption in iron metabolism
 Clinical features
 Onset of symptoms may occur early (1-2 months after
exposure) or may be delayed (about 20 years after
Headaches, neuropsychiatric manifestations (memory
disturbance, hallucinations, aggressive behavior, apathy,
irritability, social withdrawal, personality changes, and
psychosis, referred to as “manganese madness”)
Extrapyramidal symptoms: parkinsonism
Hypophonic and monotonous speech
Absence of typical parkinsonian rest tremor, but there may be a
fine, low-amplitude, high-frequency tremor
Gait: retropulsion, propulsion, often tendency to walk on toes
with elbows flexed and erect posture
Symmetric abnormally increased signal in the globus pallidus (A) and
substantia nigra (B) (may be transient)
The typical finding is really the increased pallidal signal
 Diagnosis:
 Manganese can be detected in blood for days to weeks
after exposure ceases
 Manganese levels in urine and feces may be used as a
marker for exposure within the previous few hours
 Brain MRI: high T1 signal in the globus pallidus (also
striatum and midbrain) bilaterally because of manganese
 Treatment:
 Levodopa: partial to no benefit
 Chelation with EDTA: improvement in some patients
Inorganic Mercury
 Acute intoxication: acute colitis, vomiting, renal failure,
stomatitis, little cognitive impairment except for irritability and
delirium with acute poisoning
 Chronic, low-grade toxicity: tremor, peripheral neuropathy
 Personality changes, anxiety, but little cognitive impairment
 Peripheral neuropathy: sensorimotor axonopathy,
associated with sensory loss, sensory ataxia, pain,
paresthesias, distal weakness, atrophy
Organic Mercury
 Methylmercury: better penetrance of blood-brain barrier
 Predilection for dorsal root ganglia, calcarine cortex,
and cerebellar granular layer (may also affect parietal
Organic Mercury
 Clinical features
Classic triad: gingivitis, tremor, and a neuropsychiatric illness
Cerebellar and sensory ataxia
Peripheral neuropathy
Cortical blindness from involvement of the calcarine cortex
Sensory disturbance due to involvement of dosal root ganglia
and sensory cortex
Deafness, dysarthria
Motor neuron syndrome resembling ALS, with both LMN
features (atrophy and fasciculations) and UMN features
Cognitive impairment (“mad as a hatter”): short-term memory
loss, depression, hallucinations, other features of psychosis
Organic Mercury
 Diagnosis
 Because of the distribution of mercury throughout the body,
blood mercury levels are not reliable indicators of excessive
mercury burdens
 Blood mercury levels are recommended for acute intoxications
(as elevations in blood levels will precede elevations in urine
levels) and for suspected organic poisoning
 Urinary mercury concentrations correlate well with exposure to
elemental or inorganic mercury but poor correlation with clinical
 Treatment:
 Chelation with penicillamine or DMSA
 Check fish consumption
 General principles
 Terrestrial biotoxins
 Metal intoxications
 Organic chemicals intoxications
 Marine Neurotoxins
Organic chemicals
 Acrylamide
 Hexacarbon solvents
 Carbon disulfide
 Carbon monoxide
 Toluene
 Trichloroethylene
 Methanol
 Organophosphate
 Monomeric acrylamide (not polyacrylamide) is neurotoxic
 Found in ore processing, wastewater management, gel
chromatography and in the production of polyacrylamide
 Acute intoxication with severely high exposure: seizures,
 Chronic, moderately high exposure: gradual onset of
encephalopathy and peripheral neuropathy
 Chronic, low-grade exposure: peripheral neuropathy
 Features of peripheral neuropathy
 Predominantly axonal, distal neuropathy
 Preceded by skin irritation and peeling
 Neurotoxicity may occur in abnormalities of axonal (retrograde)
transport; accumulation of neurofilaments and axonal loss are
evident in sural nerve biopsy specimens
 Predominantly sensory neuropathy, involving both small and
large fibers
 Reduced proprioceptive and vibratory sensation, sensory
ataxia, hyporeflexia, numbness, paresthesias, incoordination
 Motor involvement (distal weakness) may be present with
repetitive, high-grade exposure
Hexacarbon solvents (n-hexane and
methyl n-butyl ketone)
 Both converted to 2,5-hexanediol, which is toxic to peripheral nerve
axons and affects axonal transport (hence, giant multifocal axonal
enlargements from accumulation of neurofilaments)
 Used as paint, varnish, and glue (exposure may occur in person
sniffing glue)
 Acute exposure: euphoria, hallucinations, headaches
(encephalopathy does not occur)
 Progressive sensorimotor peripheral neuropathy with slowed
conduction velocities on electrodiagnostic testing, may look like
GBS if severe
 Despite cessation of exposure, continued progression may occur
for wks (coasting) prior to arrest and significant subsequent
Carbon disulfide
 Used in manufacturing rayon and cellophane
 Primary route of intoxication: inhalation (or ingestion)
 Acute inhalation of large amounts of the compound can produce
encephalopathy (varying severity)
 Sensorimotor peripheral neuropathy with chronic exposure:
predominantly sensory involvement, with paresthesias and numbness
and some motor involvement
 Cranial nerve involvement with vestibular, auditory, and ocular
symptoms has also been observed
 Long-term exposure could also possibly cause: minor affective or
cognitive disorder, pyramidal or extrapyramidal symptoms
(parkinsonism), optic neuropathy
 Diagnosis: urine metabolite 2-thiothiazolidine-4-carboxylic acid
Carbon monoxide
 Pure form: odorless, colorless gas
 Produced by combustion of carbon-based fuels
 Mechanism of action:
 Binds to hemoglobin with greater affinity than oxygen
(forming carboxyhemoglobin), competes with binding of
oxygen to hemoglobin
 Prevents oxygenation of tissues
 Severity of clinical presentation depends on
concentration of the gas in the exposed environment
and duration of exposure
Carbon monoxide
 Clinical features of acute intoxication may range from headaches, nausea,
dizziness to confusion, encephalopathy, pyramidal and extrapyramidal
symptoms, seizures, coma, death
 Survivors of acute intoxication who have partial or complete recovery may suffer
from delayed deterioration and recurrence of the aforementioned symptoms;
some may progress to persistent vegetative state
 The classic cherry-red discoloration of the skin and cyanosis are rarely seen
 Pathology of acute or subacute stage: diffuse cerebral edema, scattered
petechial hemorrhages in white matter and more prominent hemorrhagic foci in
the globus pallidus bilaterally
 Pathology of chronic stage: necrosis and cavitation of the globus pallidus,
confluent foci of necrosis in subcortical white matter
Carbon monoxide
CO poisoning = MRI lesions involving globus pallidus and cerebral deep WM
A) Symmetric high signal intensity lesions in bilateral globus pallidi
B) MRI in same pt as in A reveals high signal lesions in bilateral substantia nigra (dotted
arrow) in addition to bilateral pallidal lesions
C) MRI obtained 2 months after exposure shows confluent high signal lesions in the
bilateral periventricular deep white matter
 Used as solvent in paint, varnishes, thinners, glues, dyes;
used to synthesize benzene
 Acute intoxication: encephalopathy with euphoria,
incoordination and ataxia, confusion, headache
 Chronic use: euphoria, disihnibition, memory and attentional
deficits, tremor, cerebellar symptoms, optic neuropathy and
other cranial neuropathies
 Exposure to high concentrations may lead to bone marrow
 Diagnosis: hippuric acid (urine metabolite)
 Industrial solvent
 Typical presentation with high-level exposure: cranial
neuropathies, especially trigeminal neuropathy
 Trigeminal neuropathy: typically facial numbness, followed
by weakness of muscles of mastication
 There may also be ptosis, weakness of muscles of facial
expression, abnormalities of extraocular movements
 Other nonspecific symptoms: headaches, dizziness, fatigue,
 Causes necrosis of optic nerves and putamina bilaterally
 Acute intoxication
 Presentation often delayed for several hours until methanol is
metabolized to formaldehyde and formic acid
Headache, dizziness, nausea, blurred vision
Permanent visual loss may occur
Severe effects: encephalopathy, seizures, cardiopulmonary
failure, coma, death
 Pathology: likely caused by formate metabolites, hypoxemia, and
metabolic acidosis
 4-Methyl-1H-pyrazole (fomepizole) may be used to treat patients
>12 years: acts as effective inhibitor of alcohol dehydrogenase
Abnormal signal in bilateral putamen
 Mainly used in insecticides but also in fuel additives,
hydraulic fluids, and lubricants
 Acts as ACEI
 Absorbed through GI or respiratory tract or skin
*In 20% of pts
*May occur without the other
 General principles
 Terrestrial biotoxins
 Metal intoxications
 Organic chemicals intoxications
 Marine Neurotoxins
Marine neurotoxins
 Ciguatera fish poisoning
 Paralytic shellfish poisoning
 Neurotoxic shellfish poisoning
 Amnestic shellfish poisoning
 Pufferfish poisoning
Case #4
A 48-year-old woman vacationing in Jamaica for 1 month beginning in June ate local fish
daily. After 3 weeks, she and her father both developed nausea and emesis within a few
hours of eating a large, cooked barracuda
That afternoon, she began having fatigue and pruritus without rash, involving chest,
arms, and thighs. Sensation to pinprick and temperature were grossly intact by selfexamination (patient is a physician)
By the next morning, she was experiencing burning sensations in her hands and feet
bilaterally. Standing barefoot on cool floor tiles was perceived as burning pain. The
burning sensations in her hands increased with holding them under cool running water.
Drinking cold beverages caused burning sensations of her mouth and tongue
By the fifth day, the pruritus, burning dysesthesias, and paradoxical perceptions of
temperature had resolved, although her fatigue persisted, somewhat worse than usual
(past history of multiple sclerosis)
Neurologic examination after she returned home 3 weeks later was without significant
change from prior examinations (baseline generalized hyperreflexia due to multiple
sclerosis). Cerebral MRI showed no actively enhancing plaques. A few more white matter
hyperintensities were noted as interval change from her last MRI obtained 3 years before
Should you be worried? Is this MS exacerbation or intoxication?
Case #4
 Typical case of ciguatera poisoning
 Barracuda are reef predators
 Release of CTX by the microorganisms on the reef is more likely to occur in
the warmer summer months
 The onset of GI symptoms in both the patient and her father implicates the
shared fish ingestion as the source of the gGI symptoms
 The principal initial differential diagnoses would be scombroid toxicity (spoiled
fish) or a relapse of her MS
 The occurrence of pruritus without rash distinguishes ciguatera from
scombroid toxicity
 The emergence of sensory symptoms the next day, with paradoxical thermal
perceptions, is clinically confirmatory of an ingested fish toxin such as CTX
and distinguishes her sensory symptoms from a demyelinative etiology
Ciguatera fish poisoning
 Most common nonbacterial form of food poisoning
related to seafood ingestion in the United States,
Canada, and Europe
 Caused by ciguatera toxins produced by dinoflagellates
in different species of reef fish
 Ciguatoxins: increase sodium permeability via
tetrodotoxin-sensitive voltage-gated sodium
channels in nerves and muscles, causing membrane
 Maitotoxin: increases calcium permeability of
voltage-gated calcium channels
Ciguatera fish poisoning
 Clinical symptoms at onset: abdo pain and cramps,
hypersalivation, nausea, vomiting, diarrhea
 Neurologic manifestations typically follow: dysesthesias of
extremities, spreading paresthesias (including circumoral),
pruritis (either generalized or on palms and soles)
 Other: inverted sensory phenomenon (e.g., cold objects feel
warm), sensation of having loose teeth, headache, vertigo,
dizziness, dry mouth, metallic taste
 Cardiovascular manifestations: hypotension, bradycardia,
hypertension, tachycardia, arrhythmias, heart block, pulmonary
edema, congestive heart failure
 Most symptoms remit in 1 week after exposure, but certain
symptoms may persist for years after original exposure
Paralytic shellfish poisoning
 Caused by saxitoxins and related compounds from dinoflagellates
found in certain shellfish
 Toxin blocks voltage-dependent Na+ channels in nerve and
 Abrupt onset (within 30-60 min after ingestion) of symptoms:
paresthesias of face, tongue, perioral areas, and lips; vertigo;
dysarthria; ophthalmoplegia; pupillary abnormalities; ataxia
 Weakness does not occur in every patient (despite name): when
present, may involve the limbs, cranial musculature, swallowing,
and respiratory muscles
 Lack of GI illness at onset: toxin has some anticholinergic activity
and may act to slow gastric emptying; this, together with absence
of emesis, may enhance absorption of the toxin
Neurotoxic shellfish poisoning
 Caused by brevetoxins, polyether neurotoxin produced by
the marine dinoflagellate Karenia brevis and found in
 Brevetoxins
 Potent lipid-soluble neurotoxins that bind to sodium channels
on nerve and muscle cell membranes
 Produce excessive influx of sodium ions across mem- branes,
causing cellular dysfunction or death
 Similar to, but less severe than, ciguatera
 Onset of symptoms: minutes to several hours after ingestion
of contaminated food
Neurotoxic shellfish poisoning
 Illness begins with GI symptoms: nausea, vomiting,
diarrhea, abdo pain and cramping, rectal burning
 Neurologic manifestations occur concurrently with GI
 Circumoral paresthesias progressing to involve pharynx,
torso, and extremities
 Muscle weakness; myalgias; tremor; dysphagia;
 Inverted temperature sensory phenomenon (as with
ciguatera fish poisoning)
 Diagnosis: ELISA assay
Amnestic shellfish poisoning
 Caused by domoic acid: glutamate receptor agonist, excitatory
neurotoxin acting on various CNS glutamate receptors, especially
those of hippocampus
 Domoic acid: found in shellfish, including certain species of mussel
 Initial GI symptoms, usually within first 24 hours after ingestion:
nausea, vomiting, abdominal cramps, diarrhea
 Neurologic symptoms within 48 hours after ingestion: seizures,
hemiparesis, ophthalmoplegia, neuropathy, altered mentation,
 Memory impairment: anterograde and, less common but more
severe, retrograde
 Gradual improvement over 3 months
Pufferfish poisoning
Most cases associated with consumption of pufferfish from waters of Indo-Pacific ocean
Due to tetrodotoxins in various fish, including puffer fish; block voltage-gated Na+
First symptom of intoxication: perioral paresthesias, appearing 20 minutes to 3 hours
after consuming contaminated food
Paresthesias spread to face and limbs
Other symptoms: headaches, sensation of floating, epigastric pain, nausea/vomiting,
Following these symptoms: paralysis
May be respiratory distress, dysarthria, dyspnea, convulsions, altered mentation, and
death within 4 to 6 hours
Coma and seizures may occur, High mortality rate
Death may be due to cardiac arrhythmias or respiratory paralysis; patients may remain
completely alert and lucid until death
 General principles
 Peripheral neuropathy is the most common presentation of
North American neurotoxic disease
 Detailed history is important to establish causative agent
 Virtually all neurotoxic disease improves or stabilizes following
withdrawal from exposure
 Terrestrial biotoxins
 Diphteria -> GBS like, anti-toxin + antibx
 Tetanus -> spasms, trismus, anti-toxin before you wash the
wound, think about umbilical stumps in children as a source
 Envenomation -> don’t play with vipers, scorpions or spiders
 Tick paralysis -> GBS like
 Metal intoxications
 Manganese = increased T1
signal in the globus pallidus
 Organic chemicals intoxications
 Most organic chemicals are
solvents that cause
 CO poisoning = increased T2 in
globus pallidus and cerebral
deep WM
 Methanol = increased T2 signal
in putamen, visual loss
 Marine Neurotoxins
 Often cause unusual
paresthesias and may lead to
 Neurotoxicology continuum
 Mayo clinic board review

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